The basic objective of this program project is to study the mechanism of age-related changes in the pharmacological properties of the cardiovascular and central nervous systems. While there is a rich literature on differences between drug responses in young and aged organisms, little is known about the mechanisms which underlie these differences. In this program, we will study age-related changes in drug responsiveness in both man and in experimental animal models focusing on adrenergic mechanisms in the cardiovascular and central nervous systems. The molecular mechanisms for such changes, in terms of receptors, of adenylate cyclase, and of the regulation of presynaptic function will be pursued using both human and animal tissues. Physiological correlates will be examined using techniques of electrical recording and stimulation. Brain tissue transplantation will be utilized to determine the intrinsic versus extrinsic nature of any age-related central nervous changes. The major hypothesis to be pursued is that pre- and/or postsynaptic changes in the peripheral autonomic neuroeffector mechanisms or in the CNS synaptic circuitry will underlie many of the alterations in drug responsitivity seen with aging.